Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in eukaryotes. The second generation of mTOR kinase inhibitors (TORKi), directly targeting the mTOR catalytic site, are more effective than rapamycin and its analogs in cancer treatment, particularly in inducing apoptosis. However, the mechanism underlying the cytotoxic effect of TORKi remains elusive. Herein, we demonstrated that TORKi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP activation. Knocking out Rictor, a key component of mTORC2, or inhibiting p70S6K has little effect on TORKi-induced apoptosis. Conversely, increasing the eIF4E:4EBP ratio by either overexpressing eIF4E or knocking out 4EBP1/2 protected lymphoma cells from TORKi-induced cytotoxicity. Furthermore, down-regulation of MCL1 expression plays an important role in TORKi-induced apoptosis whereas BCL-2 overexpression confers resistance to TORKi treatment. We further showed that the therapeutic effect of TORKi in aggressive B-cell lymphomas can be predicted by BH3 profiling and improved by combining with pro-apoptotic drugs, especially BCL-2 inhibitors, both in vitro and in vivo. Taken together, this study provides mechanistic insight in TORKi cytotoxicity and identified a potential way to optimize its efficacy in clinical treatment of aggressive B-cell lymphoma.